结直肠癌是严重影响人类健康的消化系统恶性肿瘤。术后辅助化疗是结直肠癌常规治疗策略之一，但部分患者表现为化疗耐药，其具体作用机制不明。Ajuba在多数情况下具有促进肿瘤发生发展的作用。申请人前期研究结果提示Ajuba高表达会拮抗5-FU和阿霉素引发的细胞凋亡并加快P53降解。已知乳腺癌缺失基因1（DBC1）有稳定P53的作用，本研究进一步发现Ajuba和DBC1存在相互作用；结直肠癌细胞中DBC1过表达促进药物诱导的细胞凋亡，但Ajuba可以逆转DBC1的促凋亡作用；免疫共沉淀结果显示Ajuba会干扰DBC1与P53的相互作用。据此我们提出假说：Ajuba通过干扰DBC1对P53的稳定作用抑制化疗药诱导的结直肠癌细胞凋亡。本研究拟从分子、细胞和动物水平，探讨Ajuba负性调节P53促进结直肠癌化疗耐药的作用机制。本研究对于完善癌症发病理论、寻找治疗新靶点以及解决化疗耐药问题都将具有重要意义。

Colorectal cancer(CRC) is a prevalent gastrointestinal malignancy which threaten human health and quality of life. For unknown reasons, some patients are resistant to routine chemotherapy on postoperative CRC. In most cases, Ajuba promotes tumorgenesis and development. Our preliminary data shows that overexpression of Ajuba will lead to resistance to 5-FU and ADR induced cell apoptosis and accelerate the proteolysis of P53. We also find that Ajuba interacts with Deleted in breast cancer 1 (DBC1), a protein which can stabilize P53. DBC1 Promotes chemotherapy drugs induced apoptosis, but this effect can be reversed by Ajuba; co-precipitation indicates that Ajuba can disturb the interaction between DBC1 and P53 in a dose-dependent manner. From these observations we hypothesize that Ajuba regulates CRC cells apoptosis by interacting with DBC1. In this project , we plan to confirm our hypothesis at molecular level, celluar level and whole body level,respectively. The present study will provide theoretical and experimental evidence to elucidate the pathology of neoplasia from the new perspective , so as to provide new and effective targets for the CRC prevention and therapy.